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Substituted Amides Substituierte Amide Amides Substitues (19) TZZ_Z__T (11) EP 1 575 901 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 233/05 (2006.01) C07D 213/02 (2006.01) 10.10.2012 Bulletin 2012/41 A61K 31/44 (2006.01) (21) Application number: 03814048.9 (86) International application number: PCT/US2003/040040 (22) Date of filing: 15.12.2003 (87) International publication number: WO 2004/058145 (15.07.2004 Gazette 2004/29) (54) SUBSTITUTED AMIDES SUBSTITUIERTE AMIDE AMIDES SUBSTITUES (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR GB-A- 899 566 GB-A- 1 172 346 HU IE IT LI LU MC NL PT RO SE SI SK TR Designated Extension States: • DATABASECA [Online] CHEMICAL ABSTRACTS LT LV SERVICE, COLUMBUS, OHIO, US; HAGMANN, WILLIAM K. ET AL: "Preparation of spirocyclic (30) Priority: 19.12.2002 US 435436 P carboxamides as cannabinoid receptor modulators" XP002513691 retrieved from STN (43) Date of publication of application: Database accession no. 2003:796415 & WO 21.09.2005 Bulletin 2005/38 03/082190 A2 (MERCK & CO., INC., USA) 9 October 2003 (2003-10-09) (73) Proprietor: Merck Sharp & Dohme Corp. • DATABASECA [Online] CHEMICAL ABSTRACTS Rahway, NJ 07065-0907 (US) SERVICE, COLUMBUS, OHIO, US; HAGMANN, WILLIAM K. ET AL: "Preparation of substituted (72) Inventors: arylamides as cannabinoid-1 receptor • LIN, Linus, S. antagonists and/or inverse agonists for use as Rahway, NJ 07065-0907 (US) psychotropic drugs" XP002513692 retrieved • HAGMANN, William, K. from STN Database accession no. 2003: 837028 & Rahway, NJ 07065-0907 (US) WO 03/087037 A1 (MERCK & CO., INC., USA) 23 • KUMAR, Sanjeev October 2003 (2003-10-23) Rahway, NJ 07065-0907 (US) • YIN, Wenji Remarks: Rahway, NJ 07065-0907 (US) Thefile contains technical information submitted after • DOSS, George the application was filed and not included in this Rahway, NJ 07065-0907 (US) specification (74) Representative: Horgan, James Michael Frederic et al Merck & Co., Inc. European Patent Department Merck Sharpe & Dohme Limited Hertford Road Hoddesdon Hertfordshire EN11 9BU (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 575 901 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 575 901 B1 Description BACKGROUND OF THE INVENTION 5 [0001] Marijuana (Cannabis sativa L) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to beΔ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CB 1 and CB2. The CB 1 receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is 10 found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2- arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, an- algesia, catalepsy, anti-emesis, and appetite stimulation. [0002] The genes for the respective cannabinoid receptors have each been disrupted in mice. The CB1-/- receptor 15 knockout mice appeared normal and fertile. They were resistant to the effects ofΔ 9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome. They also demonstrated reduced motor activity and hypoalgesia. The CB2 -/- receptor knockout mice were also healthy and fertile. They were not resistant to the central nervous system mediated effects of administered Δ9-THC. There were some effects on immune cell activation, reinforcing the role for the CB2 receptor in immune system functions. 20 [0003] Excessive exposure to Δ9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation. Specific synthetic ligands for the cannabinoid receptors have been developed and have aided in the characterization of the cannabinoid receptors: CP55,940 (J. Pharmacol. Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther. 1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; Life Sci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999, 288, 582-589). The pharmacology and therapeutic potential for cannabinoid 25 receptor ligands has been reviewed (Exp. Opin. Ther. Patents 1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538; Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB1 modulator characterized as an inverse agonist or an antagonist, N-(1- piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A), in clinical trials for treatment of eating disorders at this time. There still remains a need for potent low molecular weight CB1 modulators 30 that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals. [0004] GB-B-1172 346 (Parke Davis of Company) discloses N-[ α,α-dimethyl-β-ethyl-β-(p-fluoro)phenethyl]benzamide as an appetite depressent and anoxeric. [0005] Treatment of asthma with CB1 receptor modulators (such as CB I inverse agonists) is supported by the finding that presynaptic cannabinoid CB1_receptors mediate the inhibition of noradrenaline release (in the guinea pig lung)_ 35 (Europ. J. of Pharmacology, 2001, 431 (2), 237-244). [0006] Treatment of cirrhosis of the liver with CB 1 receptor modulators is supported by the finding that a CB 1 receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride- induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure (Nature Medicine, 2001, 7 (7), 827-832). [0007] US Patents US 5,624,941 and US 6,028,084, PCT Application Nos. WO98/31227, WO98/41519, WO98/43636, 40 WO98/4363 and WO 02/076949, and EPO Application No. EP-658546 disclose substituted pyrazoles having activity against the cannabinoid receptors. [0008] PCT Application Nos. WO98/37061, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having activity against the cannabinoid receptors. [0009] PCT Application Nos. WO97/29079 and WO99/02499 disclose alkoxy- isoindolones and alkoxy-quinolones as 45 having activity against the cannabinoid receptors. [0010] US Patent US 5,532,237 discloses N- benzoyl-indole derivatives having activity against the cannabinoid recep- tors. [0011] US Patents US 4,973,587, US 5,013,837, US 5,081,122, and US 5,112,820, US 5,292,736 disclose ami- noalkylindole derivatives as having activity against the cannabinoid receptors. 50 [0012] PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazole cannabinoid receptor modulators useful for treating respiratory and non-respiratory leukocyte activation-associated disorders. [0013] PCT publications WO 01/64632, 01/64633, and 01/64634 are directed to azetidine derivatives as cannabinoid antagonists. [0014] Schultz, E.M, et al. J. Med Chem. 1967, 10, 717 and Pines, S. H. et al. J. Med. Chem. 1967, 10, 725 disclose 55 maleamic acids affecting plasma cholesterol and penicillin excretion. [0015] The compounds of the present invention are modulators of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid- 1 (CB1) receptor. In particular, compounds of the present invention are antagonists or inverse agonists of the CB1 receptor. The invention is concerned 2 EP 1 575 901 B1 with the use of these compounds to modulate the Cannabinoid-1 (CB 1) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain- Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Par- 5 kinson’s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and cirrhosis of the liver. 10 SUMMARY OF THE INVENTION [0016] The present invention is concerned with novel substituted amides of the general Formula I : 15 20 and pharmaceutically acceptable salts thereof which are antagonists and/or inverse agonists of the Cannabinoid- 1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid- 1 (CB1) 25 receptor. The invention is concerned with the use of these novel compounds to selectively
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